Medical Microbiology and Immunology

, Volume 200, Issue 1, pp 1–5

Oncomodulation by human cytomegalovirus: novel clinical findings open new roads

  • Martin Michaelis
  • Peter Baumgarten
  • Michel Mittelbronn
  • Pablo Hernáiz Driever
  • Hans Wilhelm Doerr
  • Jindrich CinatlJr.


The question whether human cytomegalovirus may affect cancer diseases has been discussed (very controversially) for decades. There are convinced believers and strict opponents of the idea that HCMV might be able to play a role in the course of cancer diseases. In parallel, the number of published reports on the topic is growing. Recently published and presented (Ranganathan P, Clark P, Kuo JS, Salamat S, Kalejta RF. A Survey of Human Cytomegalovirus Genomic Loci Present in Glioblastoma Multiforme Tissue Samples. 35th Annual International Herpes Workshop, Salt Lake City, 2010) data on HCMV detection in glioblastoma tissues and colocalisation of HCMV proteins with cellular proteins known to be relevant for glioblastoma progression motivated us to recapitulate the current state of evidence.


Cytomegalovirus Cancer Oncomodulation Tumour virus Glioblastoma Neuroblastoma 


  1. 1.
    M’Fadyan J, Hobday F (1898) Note on the experimental transmission of warts in the dog. J Comp Pathol Ther 11:341–343Google Scholar
  2. 2.
    Ciuffo G (1907) Innesto positivo con filtrato di verruca volgare. Giorn Ital Mal Venereol 48:12–17Google Scholar
  3. 3.
    Ellermann V, Bang O (1908) Experimentelle Leukämie bei Hühnern. Zentralbl Bakteriol Abt I Orig 46:595–609Google Scholar
  4. 4.
    Rous P (1911) Transmission of a malignant new growth by means of a cell-free filtrate. Am J Med Assoc 56:198Google Scholar
  5. 5.
    Javier RT, Butel JS (2008) The history of tumor virology. Cancer Res 68:7693–7706CrossRefPubMedGoogle Scholar
  6. 6.
    McLaughlin-Drubin ME, Munger K (2008) Viruses associated with human cancer. Biochim Biophys Acta 1782:127–150PubMedGoogle Scholar
  7. 7.
    Kelly E, Russell SJ (2007) History of oncolytic viruses: genesis to genetic engineering. Mol Ther 15:651–659CrossRefPubMedGoogle Scholar
  8. 8.
    Halary F, Pitard V, Dlubek D, Krzysiek R, de la Salle H, Merville P, Dromer C, Emilie D, Moreau JF, Déchanet-Merville J (2005) Shared reactivity of Vdelta2(neg) gammadelta T cells against cytomegalovirus-infected cells and tumor intestinal epithelial cells. J Exp Med 201:1567–1578CrossRefPubMedGoogle Scholar
  9. 9.
    Devaud C, Bilhere E, Loizon S, Pitard V, Behr C, Moreau JF, Dechanet-Merville J, Capone M (2009) Antitumor activity of gammadelta T cells reactive against cytomegalovirus-infected cells in a mouse xenograft tumor model. Cancer Res 69:3971–3978CrossRefPubMedGoogle Scholar
  10. 10.
    Couzi L, Levaillant Y, Jamai A, Pitard V, Lassalle R, Martin K, Garrigue I, Hawchar O, Siberchicot F, Moore N, Moreau JF, Dechanet-Merville J, Merville P (2010) Cytomegalovirus-induced gammadelta T cells associate with reduced cancer risk after kidney transplantation. J Am Soc Nephrol 21:181–188CrossRefPubMedGoogle Scholar
  11. 11.
    Erlach KC, Böhm V, Knabe M, Deegen P, Reddehase MJ, Podlech J (2008) Activation of hepatic natural killer cells and control of liver-adapted lymphoma in the murine model of cytomegalovirus infection. Med Microbiol Immunol 197:167–178CrossRefPubMedGoogle Scholar
  12. 12.
    Michaelis M, Doerr HW, Cinatl J Jr (2009) The story of human cytomegalovirus and cancer: increasing evidence and open questions. Neoplasia 11:1–9PubMedGoogle Scholar
  13. 13.
    Cinatl J Jr, Cinatl J, Radsak K, Rabenau H, Weber B, Novak M, Benda R, Kornhuber B, Doerr HW (1994) Replication of human cytomegalovirus in a rhabdomyosarcoma cell line depends on the state of differentiation of the cells. Arch Virol 138:391–401CrossRefPubMedGoogle Scholar
  14. 14.
    Cinatl J Jr, Cinatl J, Vogel JU, Rabenau H, Kornhuber B, Doerr HW (1996) Modulatory effects of human cytomegalovirus infection on malignant properties of cancer cells. Intervirology 39:259–269Google Scholar
  15. 15.
    Cinatl J Jr, Vogel JU, Cinatl J, Weber B, Rabenau H, Novak M, Kornhuber B, Doerr HW (1996) Long-term productive human cytomegalovirus infection of a human neuroblastoma cell line. Int J Cancer 65:90–96CrossRefPubMedGoogle Scholar
  16. 16.
    Cinatl J Jr, Cinatl J, Vogel JU, Kotchetkov R, Driever PH, Kabickova H, Kornhuber B, Schwabe D, Doerr HW (1998) Persistent human cytomegalovirus infection induces drug resistance and alteration of programmed cell death in human neuroblastoma cells. Cancer Res 58:367–372PubMedGoogle Scholar
  17. 17.
    Cinatl J Jr, Kotchetkov R, Scholz M, Cinatl J, Vogel JU, Driever PH, Doerr HW (1999) Human cytomegalovirus infection decreases expression of thrombospondin-1 independent of the tumor suppressor protein p53. Am J Pathol 155:285–292PubMedGoogle Scholar
  18. 18.
    Cinatl J Jr, Scholz M, Doerr HW (2005) Role of tumor cell immune escape mechanisms in cytomegalovirus-mediated oncomodulation. Med Res Rev 25:167–185CrossRefPubMedGoogle Scholar
  19. 19.
    Michaelis M, Doerr HW, Cinatl J Jr (2009) Oncomodulation by human cytomegalovirus: evidence becomes stronger. Med Microbiol Immunol 198:79–81CrossRefPubMedGoogle Scholar
  20. 20.
    Ho M (2008) The history of cytomegalovirus and its diseases. Med Microbiol Immunol 197:65–73CrossRefPubMedGoogle Scholar
  21. 21.
    Besold K, Plachter B (2008) Recombinant viruses as tools to study human cytomegalovirus immune modulation. Med Microbiol Immunol 197:215–222CrossRefPubMedGoogle Scholar
  22. 22.
    Böhm V, Podlech J, Thomas D, Deegen P, Pahl-Seibert MF, Lemmermann NA, Grzimek NK, Oehrlein-Karpi SA, Reddehase MJ, Holtappels R (2008) Epitope-specific in vivo protection against cytomegalovirus disease by CD8 T cells in the murine model of preemptive immunotherapy. Med Microbiol Immunol 197:135–144CrossRefPubMedGoogle Scholar
  23. 23.
    Campbell AE, Cavanaugh VJ, Slater JS (2008) The salivary glands as a privileged site of cytomegalovirus immune evasion and persistence. Med Microbiol Immunol 197:205–213CrossRefPubMedGoogle Scholar
  24. 24.
    Doom CM, Hill AB (2008) MHC class I immune evasion in MCMV infection. Med Microbiol Immunol 197:191–204CrossRefPubMedGoogle Scholar
  25. 25.
    Grey F, Hook L, Nelson J (2008) The functions of herpesvirus-encoded microRNAs. Med Microbiol Immunol 197:261–267CrossRefPubMedGoogle Scholar
  26. 26.
    Holtappels R, Böhm V, Podlech J, Reddehase MJ (2008) CD8 T-cell-based immunotherapy of cytomegalovirus infection: “proof of concept” provided by the murine model. Med Microbiol Immunol 197:125–134CrossRefPubMedGoogle Scholar
  27. 27.
    Lenac T, Arapović J, Traven L, Krmpotić A, Jonjić S (2008) Murine cytomegalovirus regulation of NKG2D ligands. Med Microbiol Immunol 197:159–166CrossRefPubMedGoogle Scholar
  28. 28.
    Martin H, Mandron M, Davrinche C (2008) Interplay between human cytomegalovirus and dendritic cells in T cell activation. Med Microbiol Immunol 197:179–184CrossRefPubMedGoogle Scholar
  29. 29.
    Maul GG, Negorev D (2008) Differences between mouse and human cytomegalovirus interactions with their respective hosts at immediate early times of the replication cycle. Med Microbiol Immunol 197:241–249CrossRefPubMedGoogle Scholar
  30. 30.
    Powers C, Früh K (2008) Rhesus CMV: an emerging animal model for human CMV. Med Microbiol Immunol 197:109–115CrossRefPubMedGoogle Scholar
  31. 31.
    Sacher T, Jordan S, Mohr CA, Vidy A, Weyn AM, Ruszics Z, Koszinowski UH (2008) Conditional gene expression systems to study herpesvirus biology in vivo. Med Microbiol Immunol 197:269–276CrossRefPubMedGoogle Scholar
  32. 32.
    Seckert CK, Renzaho A, Reddehase MJ, Grzimek NK (2008) Hematopoietic stem cell transplantation with latently infected donors does not transmit virus to immunocompromised recipients in the murine model of cytomegalovirus infection. Med Microbiol Immunol 197:251–259CrossRefPubMedGoogle Scholar
  33. 33.
    Stinski MF, Isomura H (2008) Role of the cytomegalovirus major immediate early enhancer in acute infection and reactivation from latency. Med Microbiol Immunol 197:223–231CrossRefPubMedGoogle Scholar
  34. 34.
    von Müller L, Mertens T (2008) Human cytomegalovirus infection and antiviral immunity in septic patients without canonical immunosuppression. Med Microbiol Immunol 197:75–82CrossRefGoogle Scholar
  35. 35.
    Waller EC, Day E, Sissons JG, Wills MR (2008) Dynamics of T cell memory in human cytomegalovirus infection. Med Microbiol Immunol 197:83–96CrossRefPubMedGoogle Scholar
  36. 36.
    Limaye AP, Kirby KA, Rubenfeld GD, Leisenring WM, Bulger EM, Neff MJ, Gibran NS, Huang ML, Santo Hayes TK, Corey L, Boeckh M (2008) Cytomegalovirus reactivation in critically ill immunocompetent patients. JAMA 300:413–422CrossRefPubMedGoogle Scholar
  37. 37.
    Söderberg-Nauclér C (2008) HCMV microinfections in inflammatory diseases and cancer. J Clin Virol 41:218–223CrossRefPubMedGoogle Scholar
  38. 38.
    Cinatl J Jr, Vogel JU, Kotchetkov R, Wilhelm Doerr H (2004) Oncomodulatory signals by regulatory proteins encoded by human cytomegalovirus: a novel role for viral infection in tumor progression. FEMS Microbiol Rev 28:59–77CrossRefPubMedGoogle Scholar
  39. 39.
    Paulus C, Nitzsche A, Nevels M (2010) Chromatinisation of herpesvirus genomes. Rev Med Virol 20:34–50CrossRefPubMedGoogle Scholar
  40. 40.
    Terhune SS, Moorman NJ, Cristea IM, Savaryn JP, Cuevas-Bennett C, Rout MP, Chait BT, Shenk T (2010) Human cytomegalovirus UL29/28 protein interacts with components of the NuRD complex which promote accumulation of immediate-early RNA. PLoS Pathog 6:e1000965CrossRefPubMedGoogle Scholar
  41. 41.
    Komano J, Sugiura M, Takada K (1998) Epstein-Barr virus contributes to the malignant phenotype and to apoptosis resistance in Burkitt’s lymphoma cell line Akata. J Virol 72:9150–9156PubMedGoogle Scholar
  42. 42.
    Kassis J, Maeda A, Teramoto N, Takada K, Wu C, Klein G, Wells A (2002) EBV-expressing AGS gastric carcinoma cell sublines present increased motility and invasiveness. Int J Cancer 99:644–651CrossRefPubMedGoogle Scholar
  43. 43.
    Abdulkarim B, Sabri S, Zelenika D, Deutsch E, Frascogna V, Klijanienko J, Vainchenker W, Joab I, Bourhis J (2003) Antiviral agent cidofovir decreases Epstein-Barr virus (EBV) oncoproteins and enhances the radiosensitivity in EBV-related malignancies. Oncogene 22:2260–2271CrossRefPubMedGoogle Scholar
  44. 44.
    Lau SK, Chen YY, Chen WG, Diamond DJ, Mamelak AN, Zaia JA, Weiss LM (2005) Lack of association of cytomegalovirus with human brain tumors. Mod Pathol 18:838–843CrossRefPubMedGoogle Scholar
  45. 45.
    Poltermann S, Schlehofer B, Steindorf K, Schnitzler P, Geletneky K, Schlehofer JR (2006) Lack of association of herpesviruses with brain tumors. J Neurovirol 12:90–99CrossRefPubMedGoogle Scholar
  46. 46.
    Sabatier J, Uro-Coste E, Pommepuy I, Labrousse F, Allart S, Trémoulet M, Delisle MB, Brousset P (2005) Detection of human cytomegalovirus genome and gene products in central nervous system tumours. Br J Cancer 92:747–750CrossRefPubMedGoogle Scholar
  47. 47.
    Slinger E, Maussang D, Schreiber A, Siderius M, Rahbar A, Fraile-Ramos A, Lira SA, Söderberg-Nauclér C, Smit MJ (2010) HCMV-encoded chemokine receptor US28 mediates proliferative signaling through the IL-6-STAT3 axis. Sci Signal 3:ra58Google Scholar
  48. 48.
    Lucas KG, Bao L, Bruggeman R, Dunham K, Specht C (2010) The detection of CMV pp65 and IE1 in glioblastoma multiforme. J Neurooncol 2010 Sep 5. [Epub ahead of print]Google Scholar
  49. 49.
    Strååt K, Liu C, Rahbar A, Zhu Q, Liu L, Wolmer-Solberg N, Lou F, Liu Z, Shen J, Jia J, Kyo S, Björkholm M, Sjöberg J, Söderberg-Nauclér C, Xu D (2009) Activation of telomerase by human cytomegalovirus. J Natl Cancer Inst 101:488–497CrossRefPubMedGoogle Scholar
  50. 50.
    Cobbs CS, Harkins L, Samanta M, Gillespie GY, Bharara S, King PH, Nabors LB, Cobbs CG, Britt WJ (2002) Human cytomegalovirus infection and expression in human malignant glioma. Cancer Res 62:3347–3350PubMedGoogle Scholar
  51. 51.
    Mitchell DA, Xie W, Schmittling R, Learn C, Friedman A, McLendon RE, Sampson JH (2008) Sensitive detection of human cytomegalovirus in tumors and peripheral blood of patients diagnosed with glioblastoma. Neuro Oncol 10:10–18CrossRefPubMedGoogle Scholar
  52. 52.
    Scheurer ME, Bondy ML, Aldape KD, Albrecht T, El-Zein R (2008) Detection of human cytomegalovirus in different histological types of gliomas. Acta Neuropathol 116:79–86CrossRefPubMedGoogle Scholar
  53. 53.
    Cinatl J Jr, Nevels M, Paulus C, Michaelis M (2009) Activation of telomerase in glioma cells by human cytomegalovirus: another piece of the puzzle. J Natl Cancer Inst 101:441–443CrossRefPubMedGoogle Scholar
  54. 54.
    Prins RM, Cloughesy TF, Liau LM (2008) Cytomegalovirus immunity after vaccination with autologous glioblastoma lysate. N Engl J Med 359:539–541CrossRefPubMedGoogle Scholar
  55. 55.
    Aarnisalo J, Ilonen J, Vainionpää R, Volanen I, Kaitosaari T, Simell O (2003) Development of antibodies against cytomegalovirus, varicella-zoster virus and herpes simplex virus in Finland during the first 8 years of life: a prospective study. Scand J Infect Dis 35:750–753CrossRefPubMedGoogle Scholar
  56. 56.
    Wertheim P, Voute PA (1976) Neuroblastoma, Wilms’ tumor, and cytomegalovirus. J Natl Cancer Inst 57:701–703PubMedGoogle Scholar
  57. 57.
    Nigro G, Schiavetti A, Booth JC, Clerico A, Dominici C, Krzysztofiak A, Castello M (1995) Cytomegalovirus-associated stage 4S neuroblastoma relapsed stage 4. Med Pediatr Oncol 24:200–203CrossRefPubMedGoogle Scholar
  58. 58.
    Casciano I, Mazzocco K, Boni L, Pagnan G, Banelli B, Allemanni G, Ponzoni M, Tonini GP, Romani M (2002) Expression of DeltaNp73 is a molecular marker for adverse outcome in neuroblastoma patients. Cell Death Differ 9:246–251CrossRefPubMedGoogle Scholar
  59. 59.
    Allart S, Martin H, Detraves C, Terrasson J, Caput D, Davrinche C (2002) Human cytomegalovirus induces drug resistance and alteration of programmed cell death by accumulation of deltaN-p73alpha. J Biol Chem 277:29063–29068CrossRefPubMedGoogle Scholar
  60. 60.
    Blaheta RA, Beecken WD, Engl T, Jonas D, Oppermann E, Hundemer M, Doerr HW, Scholz M, Cinatl J Jr (2004) Human cytomegalovirus infection of tumor cells downregulates NCAM (CD56): a novel mechanism for virus-induced tumor invasiveness. Neoplasia 6:323–331CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Martin Michaelis
    • 1
  • Peter Baumgarten
    • 2
  • Michel Mittelbronn
    • 2
  • Pablo Hernáiz Driever
    • 3
  • Hans Wilhelm Doerr
    • 1
  • Jindrich CinatlJr.
    • 1
  1. 1.Institut für Medizinische VirologieKlinikum der Goethe-UniversitätFrankfurt am MainGermany
  2. 2.Neurological Institute (Edinger Institute)Goethe UniversityFrankfurt am MainGermany
  3. 3.Department of Pediatric Oncology/HematologyCharité-Universitätsmedizin BerlinBerlinGermany

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